Treatment of KRAS-Mutated Pancreatic Cancer: New Hope for the Patients?

Abstract

Pancreatic cancer, specifically pancreatic ductal adenocarcinoma (PDAC), ranks among the most lethal malignancies, with a 5-year survival rate of under 10%. The most prevalent KRAS mutations occur in three hotspot residues: glycine-12 (G12), glycine-13 (G13), and glutamine-61 (Q61), leading to the constant activation of the Ras pathway, making them the primary focus in oncologic drug development. Selective KRAS G12C inhibitors (e.g., sotorasib, adagrasib) have demonstrated moderate efficacy in clinical trials; however, this mutation is infrequent in PDAC. Emerging therapies targeting KRAS G12D and G12V mutations, such as MRTX1133, PROTACs, and active-state inhibitors, show promise in preclinical studies. Pan-RAS inhibitors like ADT-007, RMC-9805, and RMC-6236 compounds provide broader coverage of mutations. Their efficacy and safety are currently being investigated in several clinical trials. A major challenge is the development of resistance mechanisms, including secondary mutations and pathway reactivation. Combination therapies targeting the RAS/MAPK axis, SHP2, mTOR, or SOS1 are under clinical investigation. Immunotherapy alone has demonstrated limited effectiveness, attributed to an immunosuppressive tumor microenvironment, although synergistic effects are noted when paired with KRAS-targeted agents. Furthermore, KRAS mutations reprogram cancer metabolism, enhancing glycolysis, macropinocytosis, and autophagy, which are being explored therapeutically. RNA interference technologies have also shown potential in silencing mutant KRAS and reducing tumorigenicity. Future strategies should emphasize the combination of targeted therapies with metabolic or immunomodulatory agents to overcome resistance and enhance survival in KRAS-mutated PDAC.

Keywords: ADT-007; KRAS mutations; MRTX1133; RMC-6236; RMC-9805; RNAi; adagrasib; pan-RAS inhibitors; pancreatic cancer; sotorasib.

Figure 1

The cell regulation of KRAS protein. When these receptors are activated, guanine nucleotide exchange factors (GEFs) promote GDP-GTP exchange on Ras, switching it to an active state. It is inactivated when GTP is hydrolyzed to GDP, a process sped up by GTPase-activating proteins (GAPs). Ras mutations are commonly selected in cancer because Ras activates multiple effector pathways that promote oncogenic transformation. These include the MAPK cascade (RAF–MEK—ERK), PI3K/AKT/mTOR, and Ral guanine nucleotide exchange factors pathway [31,34,35,36,37,38]. Abbreviations: KRAS—Kirsten rat sarcoma viral oncogene; RTK—receptor tyrosine kinase; GAPs—GTPase-activating proteins; GEFs—guanine nucleotide exchange factors; GDP—guanosine diphosphate; GTP—guanosine triphosphate; RAF—rapid fibrosarcoma; ERK—extracellular signal-regulated kinase.

Figure 2

Common KRAS mutations in PDAC. Chart shows the approximate prevalence of major KRAS mutations in PDAC. The most frequent subtype is G12D (39.2%), followed by G12V (32.5%) and G12R (17.1%). Less common mutations include Q61H (5%), G12C (1.7%), and other mutations (4.5%). Based on [47].

Figure 3

Mechanism of formation and action of siRNA. Dicer, by splitting dsRNAs, forms molecules with 20–27 base pairs in length called siRNAs. Created siRNAs are integrated into a complex structure made up of AGO2 and RISC. Next, the targeted mRNA is bound to the antisense strand of the siRNA, leading to its cleavage. This mechanism prevents the translation of the targeted mRNA into a functional protein [105]. Abbreviations: dsRNA—long double-strand RNA; Dicer—dsRNA-specific RNase; siRNA—small interfering RNA; AGO2—Argonaute 2; RISC—RNA-induced silencing complex.

Figure 4

Novel treatment strategies for KRAS-mutated PDAC. Specific mutation-targeted strategies are currently being investigated, including selective inhibitors for KRAS G12C (sotorasib, adagrasib), KRAS G12D (MRTX1133, HRS-4642, PROTACs) and KRAS G12V (ternary complex formation with cyclophilin A, KRAS G12V and KRAS-inhibitor). Pan-RAS inhibitors (e.g., BI-2865, ADT-007, RMC-6236, YL-17231) target a broader range of KRAS isoforms, which may be more effective in heterogenous PDAC. Additional approaches involve RNA interference (siRNA therapies such as siG12D-LODER, nanoparticle-based delivery systems, PLGA microparticles, EFTX-G12V, and iExosomes), miRNAs (miR-217, miR-96, miR-873), and modulation of metabolic and autophagy pathways (e.g., devimistat, UBL4A, UAMC-2526). Based on [61,66,67,70,74,80,85,86,89,90,106,108,109,112,114,117,119,125,128,131,176,181,185]. Abbreviations: CypA—Cyclophilin A; PLGA—Poly(lactic-co-glycolic acid); siRNA—Small interfering RNA; miRNA—MicroRNA; KRAS—Kirsten rat sarcoma viral oncogene homolog; PDAC—Pancreatic ductal adenocarcinoma.